Processes for preparing 3-arylsulfur hydroxamic acids

ABSTRACT

This invention provides processes for the preparation of a compound of Formula I:  
     Y—C(═O)—C(R 1 )(R 2 )—CH 2 —S(O) n R 3    
     wherein:  
     Y is hydroxy or XONX, where each X is independently hydrogen, lower alkyl or lower acyl;  
     R 1  is hydrogen or lower alkyl;  
     R 2  is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, or R 1  and R 2  together with the carbon atom to which they are attached form a cycloalkyl or heterocyclo group;  
     R 3  is aryl; and  
     n is  0, 1  or  2.    
     The invention also provides novel aryl haloalkyl sulfide intermediates useful for the preparation of compounds of Formula I and novel methods of preparing aryl alkyl sulfides.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit under 35 U.S.C. 119(e) ofU.S. Provisional Application Ser. No. 60/089,778, filed Jun. 18, 1998,hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to methods of preparing matrixmetalloprotease inhibitors, particularly 3-arylsulfur hydroxamic acids.

[0004] 2. Background Information

[0005] I. MMP Inhibitors

[0006] Matrix metalloproteases (“MMPs”) are a family of proteases(enzymes) involved in the degradation and remodeling of connectivetissues. MMP expression is stimulated by growth factors and cytokines inthe local tissue environment, where these enzymes act to specificallydegrade protein components of the extracellular matrix, such ascollagen, proteoglycans (protein core), fibronectin and laminin.Excessive degradation of extracellular matrix by MMPs is implicated inthe pathogenesis of many diseases, including rheumatoid arthritis,osteoarthritis, multiple sclerosis, bone resorptive diseases (such asosteoporosis), chronic obstructive pulmonary disease, cerebralhemorrhaging associated with stroke, periodontal disease, aberrantangiogenesis, tumor invasion and metastasis, corneal and gastriculceration, ulceration of skin, aneurysmal disease, and in complicationsof diabetes.

[0007] Furthermore, inhibitors of MMP also are known to substantiallyinhibit the release of tumor necrosis factor (TNF) from cells andtherefore may be used in the treatment of conditions mediated by TNF.Such uses include, but are not limited to, the treatment ofinflammation, fever, cardiovascular effects, hemorrhage, coagulation andacute phase response, cachexia and anorexia, acute infections, shockstates, restenosis, graft versus host reactions and autoimmune disease.

[0008] MMP inhibition is, therefore, recognized as a good target fortherapeutic intervention. Consequently, inhibitors of MMPs provideuseful treatments for diseases associated with the excessive degradationof extracellular matrix and diseases mediated via TNF and several MMPinhibitors are currently being developed for such uses.

[0009] One particular class of MMP inhibitors are the 3-arylsulfurhydroxamic acids described in EP 0 780 386 A1, published Jun. 25, 1997.This publication discloses MMP inhibitors of Formula I,

Y—C(═O)—C(R¹)(R²)—CH₂—S(O)_(n)R³

[0010] where n, Y, R¹, R² and R³ are as described below in the Summaryof the Invention.

[0011] WO 97/24117, published Jul. 10, 1997, discloses 3-aryl sulfurhydroxamic acids of formula,HON(H)—C(═O)—C_(p)(R₁)(R₂)—C(R₃)(R₄)—S(O)_(n)—C_(m)(R₅)(R₆)—Ar, where p,m, n and R₁, R₂, R₃, R₄, R₅, R₆ and Ar are as described in WO 97/24117.

[0012] WO 98/05635, published Feb. 12, 1998, discloses 3-arylsulfurhydroxamic acids of formula B—S(O)₀₋₂—CHR¹—CH₂—CO—NHOH, where B and R¹are as described in in WO 98/05635.

[0013] WO 98/13340, published Apr. 2, 1998, discloses β-sulfonylhydroxamic acids of HONHC(═O)—CHR₂—CH₂—S(O)₂R₁ where R₁ and R₂ are asdescribed therein.

[0014] However, the processes disclosed in these publications forpreparing 3-arylsulfur hydroxamic acids proceed via the nucleophilicattack of a thiol on the β-carbon of a carboxylate derivative, eitherdisplacing a leaving group at the β-carbon or performing a Michaelreaction on an α,β unsaturated ester or acid. Thus, the disclosedprocesses are limited by the availability of the corresponding thiolsand the β-substituted carboxylate derivatives and α,β unsaturatedesters. This invention provides novel processes and novel intermediatesthat are not dependent on the availability of the reagents used in theabove publications.

[0015] The use of 3-arylsulfonyl hydroxamic acids as MMP inhibitors isalso described in WO 97/49679 A1, published Dec. 31, 1997.

[0016] II. Preparation of Aryl Alkyl Sulfides

[0017] Aryl haloalkyl sulfides are valuable intermediates in syntheticorganic processes and they are commonly made by free radicalhalogenation of a precursor aryl alkyl sulfide. The aryl alkyl sulfideis in turn typically available via sulfonation of a precursor arylhydrocarbon, reduction to an aryl thiol and alkylation of the thiol. Itwould be useful to have methods of directly converting arylsulfonylderivatives to aryl methyl sulfides.

[0018] There have been various reports of the reactions between trialkylphosphites and aryl sulfonyl derivatives. See, for example, R. W.Hoffman, T. R. Moore and B. J. Kagan, (“The Reaction between TriethylPhosphite and and Alkyl and Aryl Sulfonyl Chlorides”) J. Am. Chem. Soc.,78:6413-6414 (1956); J. M. Klunder and K. Barry Sharpless, (“AConvenient Synthesis of Sulfinate Esters from Sulfonyl Chlorides”) J.Org. Chem., 52:2598-2602 (1987); and J. Cadogan (“Oxidation of TervalentOrganic Compounds of Phosphorous”) Quarterly Reviews, 16:208-239 (1962).The reaction of benzensulfenyl chloride with triethylphosphite to yieldethyl phenyl sulfide has also been reported, T. Mukaiyama and H. Ueki,(“The Reactions of Sulfur-containing Phosphonium Salts”) Tetr. Lett.,35:5429-5431 (1967). Aryl sulfonyl chlorides have also been converted toaryl methyl sulfides in three steps by treatment of an aryl sulfonylchloride with lithium diphenylphosphide, Ph₂PLi, to afford aP-diphenyl-aryl sulfophosphamide is followed by cathodic reduction andmethylation of the resulting aryl thiolate, J. Pilard and J. Simonet.(“The Cathodic Cleavage of the S-P Bond. Synthesis and ElectrochemicalBehaviour of Sulfonamide Phosphorous Analogues”), Tetr. Lett.,38(21):3735-3738 (1997).

SUMMARY OF THE INVENTION

[0019] In one aspect, this invention provides processes for thepreparation of a compound of Formula I:

Y—C(═O)—C(R¹)(R²)—CH₂—S(O)_(n)R³

Formula I

[0020] wherein:

[0021] Y is hydroxy or XONX—, where each X is independently hydrogen,lower alkyl or lower acyl;

[0022] R¹ is hydrogen or lower alkyl;

[0023] R² is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, or R¹ and R² together with the carbon atom to whichthey are attached form a cycloalkyl or heterocyclo group;

[0024] R³ is aryl; and

[0025] n is 0, 1 or 2;

[0026] comprising the steps of:

[0027] (1) alkylating a compound of Formula II,

RO—C(═O)—CH(R¹)(R²)

Formula II

[0028] where R is alkyl or hydrogen, with an arylmethylthio derivativeof Formula III, ArSCH₂—Z, wherein Ar is an aryl group and Z is a leavinggroup, to provide a compound of Formula IV,

RO—C(═O)—C(R¹)(R²)—CH₂SAr, and

Formula IV

[0029] (2) converting the compound of Formula IV to a compound ofFormula I by replacing the group RO— with XONH— and optionally oxidizingthe ArS group as necessary in either order.

[0030] The invention also provides novel aryl haloalkyl sulfide and arylalkyl sulfide intermediates useful for the preparation of compounds ofFormula I and novel methods of preparing aryl alkyl sulfides.

DETAILED DESCRIPTION OF THE INVENTION

[0031] Definitions

[0032] As used herein, the term “(Cr_(p-q)) alkyl” means a linear orbranched fully-saturated hydrocarbon radical having p to q carbon atoms;for example, a “C₁₋₄ alkyl” means a linear or branched fully saturatedhydrocarbon radical having one to four carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, or tert-butyl.

[0033] Unless otherwise specified, the term “lower alkyl” means a C₁₋₄alkyl radical.

[0034] As used herein, the term “(C₃₋₆) cycloalkyl” means a fullysaturated cyclic hydrocarbon radical of three to six ring carbon atoms,e.g., cyclopropyl, cyclopentyl and the like.

[0035] As used herein, the term “lower acyl” refers to a group —C(═O)R,where R is a (C₁₋₄)alkyl radical.

[0036] As used herein, the term “loweralkoxy” refers to a group —OR,where R is a (C₁₋₄)alkyl radical.

[0037] As used herein, the term “(C₇₋₁₀)alkoxy” refers to a group OR,where R is a (C₇₋₁₀)alkyl radical.

[0038] As used herein, the term “aryl” means a monovalent monocyclic orbicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, andoptionally substituted independently with one, two or three substituentsselected from alkyl, haloalkyl, cycloalkyl, halo, nitro, cyano,optionally substituted phenyl, —OR (where R is hydrogen, alkyl,haloalkyl, cycloalkyl, optionally substituted phenyl), acyl, —COOR(where R is hydrogen or alkyl). More specifically the term arylincludes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, andderivatives thereof.

[0039] As used herein, the term “arylene” means a divalent monocyclic orbicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, andoptionally substituted independently with one, two or three substituentsselected from alkyl, haloalkyl, cycloalkyl, halo, nitro, cyano,optionally substituted phenyl, —OR (where R is hydrogen, alkyl,haloalkyl, cycloalkyl, optionally substituted phenyl), acyl, —COOR(where R is hydrogen or alkyl). More specifically the term arylincludes, but is not limited to, 1,4-phenylene and 1,2 phenylene.

[0040] “Optionally substituted phenyl” means a phenyl group which isoptionally substituted independently with one, two or three substituentsselected from alkyl, haloalkyl, halo, nitro, cyano, —OR (where R ishydrogen or alkyl), —NRR′ (where R and R′ are independently of eachother hydrogen or alkyl), —COOR (where R is hydrogen or alkyl) or—CONR′R″ (where R′ and R″ are independently selected from hydrogen oralkyl).

[0041] “Heterocyclo” means a saturated monovalent cyclic group of 3 to 8ring atoms in which one or two ring atoms are heteroatoms selected fromN, O, or S(O)_(n), where n is an integer from 0 to 2, the remaining ringatoms being C. The heterocyclo ring may be optionally fused to a benzenering or it may be optionally substituted independently with one or moresubstituents, preferably one or two substituents, selected from alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, halo, cyano,acyl, monosubstituted amino, disubstituted amino, carboxy, oralkoxycarbonyl. More specifically the term heterocyclo includes, but isnot limited to, pyrrolidino, piperidino, morpholino, piperazino,tetrahydropyranyl, and thiomorpholino, and the derivatives thereof.

[0042] “Leaving group” has the meaning conventionally associated with itin synthetic organic chemistry i.e., an atom or group capable of beingdisplaced by a nucleophile and includes halogen, alkanesulfonyloxy,arenesulfonyloxy, amino, alkylcarbonyloxy, arylcarbonyloxy, such aschloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, N,O—dimethylhydroxylamino, acetoxy, and the like.

[0043] In one aspect, this invention provides a process for thepreparation of a compound of Formula I:

Y—C(═O)—C(R¹)(R²)—CH₂—S(O)_(n)R³

Formula I

[0044] wherein:

[0045] Y is hydroxy or XONX, where each X is independently hydrogen,lower alkyl or lower acyl;

[0046] R¹ is hydrogen or lower alkyl;

[0047] R² is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, or R¹ and R² together with the carbon atom to whichthey are attached form a cycloalkyl or heterocyclo group;

[0048] R³ is aryl; and

[0049] n is , 1 or 2;

[0050] comprising the steps of:

[0051] (1) alkylating a compound of Formula II,

RO—C(═O)—CH(R¹)(R²)

Formula II

[0052] where R is alkyl or hydrogen, with an arylmethylthio derivativeof Formula III, ArSCH₂—Z, wherein Ar is an aryl group and Z is a leavinggroup, to provide a compound of Formula IV,

RO—C(═O)—C(R¹)(R²)—CH₂SAr and

Formula IV

[0053] (2) converting the compound of Formula IV to a compound ofFormula I by replacing the group RO— with XONH— and optionally oxidizingthe ArS group as necessary in either order.

[0054] Unlike the methods disclosed in EP 0 780 386 A1, published Jun.25, 1997, WO 97/24117, published Jul. 10, 1997, WO 98/05635, publishedFeb. 12, 1998 and WO 98/13340, published Apr. 2, 1998, for the synthesisof 3-arylsulfur hydroxamic acids, the processes of the present inventionproceed via the alkylation of the α-carbon of a carbonyl group with ahalomethyl aryl sulfide. The invention also provides novel halomethylaryl sulfides, such as chlorophenoxyphenyl chloromethyl sulfide andmethods for their preparation. Thereby, the inventors are able toprepare compounds of Formula I by novel processes not previouslyavailable.

[0055] These reaction processes are shown in Scheme A, below.

[0056] Compounds of Formula IV may be converted to compounds of FormulaI by conversion of the carboxyl group to a group —C(═O)—L where L is aleaving group under nucleophilic displacement conditions followed bydisplacement of L with hydroxylamine (or an alkylated derivative). Theresulting hydroxamic acid is then oxidized as necessary to give thedesired sulfoxide or sulfone. Oxidation to the sulfoxide is accomplishedby treatment with mild oxidizing agents such as sodium or potassiummetaperiodate or one equivalent potassium peroxymonosulfate (Oxone™).Other oxidants that may be used include peracids, (e.g. performic orperacetic acid) or sodium perborate/organic acid mixtures (e.g.performic or peracetic acid). The reaction may be halted at thesulfoxide stage by limiting the quantity of reagents, temperature andreaction time. Further oxidation to the sulfone is accomplished bytreatment under more vigorous conditions with organic peracids such asm-chloroperbenzoic acid or two equivalents of sodium peroxymonosulfate.Alternatively, other oxidizing agents such as perborates, e.g., sodiumperborate, in a carboxylic acid solvent such as formic, acetic orpropionic acid may be used. These last two steps may also be reversed,i.e., oxidation of the sulfur moiety may precede conversion of the acidto the hydroxamate. However, overall yields are usually higher with theformer sequence.

[0057] Compounds of Formula II, RO—C(═O)—CH(R¹)(R²), can be purchasedfrom commercial suppliers or are readily available by publishedprocedures known to one of skill in the art. See, for example, EP 0 780386 A1.

[0058] Compounds of Formula III, ArSCH₂—Z, are made by oxidation of theprecursor arylmethylthioether. Compounds ArSCH₂Cl are made by oxidationwith sulfuryl chloride in aprotic solvents such as methylene chloride,t-butylmethyl ether or hexane. The oxidation may be done at roomtemperature or at lower temperatures, e.g., from about 0-10° C. Otherreagents, such-as N-chlorosuccinimide, may also be used. CompoundsArSCH₂Br are made by oxidation with sulfuryl bromide or other reagentssuch as N-bromosuccinimide.

[0059] Compounds of Formula III, ArSCH₂—Z, where Z is chloro or bromomay also be made from the corresponding thiol as shown below:

[0060] Arylmethylthioethers are generally available either fromcommercial vendors or published literature procedures. For example, theymay be made by sulfonylating an aryl compound to the correspondingsulfonic acid, reducing the sulfonic acid to a thiol and methylating thethiol.

[0061] Alternatively, as shown in Scheme B, the inventors haveunexpectedly discovered that arylsulfonyl halides can be converteddirectly to arylmethylthioethers in one step by treatment withtrimethylphosphite. The conversion proceeds best if thetrimethylphosphite treatment is followed by treatment with a base.Either an organic base such as an alkylamine (e.g. triethylamine) or ahydroxylic base such as an alkali metal hydroxide or an alkaline earthmetal hydroxide may be used. However, the conversion may also beaccomplished, albeit in somewhat lower yield, without the addition of abase. In such processes, the yield of the aryl methyl sulfide may beincreased by heating to elevated temperatures, e.g., as high as about100° C., preferably as high as about 130° C. (internal temperature).Consequently, the invention also provides a novel method of preparingaryl methyl sulfides by directly reducing/alkylating an arylsulfonylhalide with trimethyl phosphite.

[0062] The method is particularly useful for for forming compounds offormula ArSCH₃, wherein Ar has the formula Ar¹—Ar², where Ar¹ and Ar²are phenyl rings, each independently optionally substituted and A is abond, CH₂ or —O—, and more particularly where, A is oxygen, Ar¹ isphenyl and Ar² is 4-chlorophenyl.

[0063] Subsequent halogenation of ArSCH₃ then provides key intermediatesof formula ArSCH₂—X where X is halo. Useful key intermediates includethose where Ar is Ar¹—A—Ar , wherein Ar¹ and Ar² are independentlyoptionally substituted phenyl, X is halo, A is oxygen, or CH₂. Aparticularly useful intermediate is that wherein Ar¹ is phenyl, Ar² ishalophenyl, and A is oxygen.

[0064] Alkylation of a compound of Formula II with a compound of FormulaIII may be accomplished by conditions known to one of skill in the artsuch as converting a compound of Formula II to an enolate or enolfollowed by reaction with a compound of Formula III. Other conditionsinclude forming the dianion of the acid (i.e., compound of Formula IIwhere R═H) by treatment with two equivalents of a base such as lithiumdiisopropylamide or lithium hexamethyldisilazide and alkylating with oneequivalent of a compound of Formula III.

[0065] In one embodiment, a compound of Formula II was converted to asilylketene acetal as shown in Reaction Scheme C (where Silyl representsa silyl group), followed by Mukaiyama coupling of the acetal with acompound of Formula III. The coupling is generally done in an anhydrousaprotic solvent such as a halocarbon or hydrocarbon (methylene chloride,chloroform, benzene, toluene etc.) in the presence of a Lewis acid suchas zinc chloride, zinc bromide, zinc iodide, ferric bromide or titaniumtetrachloride. Silylketene acetals may be readily prepared fromcompounds of Formula II by procedures such as those described in C.Ainsworth, F. Chen, Y. N. Kuo “Ketene Alkyltrialkylsilyl Acetals:Synthesis, Pyrolysis and NMR Studies”) J. Organometallic Chem., 46:59-87(1972). A variety of silyl protecting groups, e.g.,t-butyldimethylsilyl, trimethylsilyl, etc. may be used. Silylketeneacetals can be formed from either the ester (R═alkyl) or acids (R═H) ofFormula II. Formation of the silylketene acetal from the acid may beaccomplished using two equivalents of base and quenching with twoequivalents of the silylating, reagent. Subsequent alkylation with acompound of Formula III followed by a hydrolytic work up then directlyyields a carboxylic acid of Formula IV. Reagents that may be used toform the silylketene acetal include trimethylysilyl triflate,trimethylsilyl chloride or bromide, tert-butyldimethylsilyl chloride andbis-trimethylsilyl acetamide.

[0066] Alternatively, an enolate of a compound of Formula II may bedirectly alkylated with a compound of Formula III, thus avoiding theintermediacy of the silylketene acetal. The enolate is formed understandard conditions, by treatment with a non-nucleophilic organic basesuch as lithium diisopropylamide or lithium hexamethyldisilazide, or ametal hydride such potassium hydride, under anhydrous conditions,typically at room temperature, in a polar aprotic solvent such astetrahydrofuran, dimethoxyethane or glyme and the like. Subsequentaddition of a compound of a Formula III followed by heating if necessaryto reflux temperatures, e.g., 60-80° C., provides an alkylated productof Formula IV. The enolate may also be formed from the correspondingα-bromoester of a compound of Formula II by treatment with zinc to formthe zinc enolate which can then be alkylated.

[0067] Though the processes described herein may be used to prepare avariety of 3-arylsulfur hydroxamic acids and their corresponding carboxyand ester derivatives, they are particularly useful for preparingcompounds of Formula I wherein the aryl group Ar is of the formulaAr¹—A—Ar², wherein Ar¹ and Ar² are phenyl rings, each independentlyoptionally substituted and A is a bond, —CH₂— or —O—.

[0068] Other useful compounds that may be made by the methods of theinvention include compounds of Formula I where R¹ and R² together withthe carbon atom to which they are attached form a cycloalkyl orheterocyclo group, particularly a tetrahydropyranyl group.

[0069] Additional useful hydroxamic acids that may be prepared includethose that are α, α-disubstituted, i.e., neither R¹ nor R² are hydrogen.

[0070] Utility and Administration

[0071] As described earlier, the compounds made by these processes areMMP inhibitors, useful in treating a variety of diseases as disclosed inEP 0 780 386 A1, published Jun. 25, 1997; WO 97/24117, published Jul.10, 1997; and WO 98/05635, published Feb. 12, 1998.

[0072] The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

[0073] Abbreviations used in the examples are defined as follows: “DMF”for dimethylformamide, “NaOH” for sodium hydroxide, “DMSO” fordimethylsulfoxide, “PTLC” for preparatory thin layer chromatography,“EtOAc” for ethyl acetate, “LDA” for lithium diisopropylamide and“TMSCl” for trimethylsilylchloride.

EXAMPLE Synthesis of4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N-hydroxycarboxamido)Tetrahydropyran

[0074] Scheme D shows a representative method of this invention for thepreparation of 14,4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N-hydroxycarboxamido)tetrahydropyran, a compound of Formula I, wherein:

[0075] Y is NHOH;

[0076] R¹ and R² together with the carbon atom to which they areattached represent a tetrahydropyran-4-yl group; and

[0077] R³ is 4-chlorophenoxyphenyl.

[0078] Although Scheme D is directed towards the synthesis of a specific3-arylsulfur hydroxamic acid, it is to be understood that a similar setof reactions can be used to prepare other arylsulfur hydroxamic acids,carboxylic acids and esters by substituting appropriate startingmaterials and reagents as outlined in Reaction Schemes A-C.

[0079] A. Preparation of 4-(4-Chlorophenoxy)phenyl Chloromethyl Sulfide

[0080] Step 1

[0081] Diphenylether 1, is available from Aldrich (Milawaukee, Wis.) andcan be converted to 4-(4′-chlorophenoxy)phenyl sulfonylchloride,compound 3, using known procedures, such as described in WO 97/20824.

[0082] Step 2

[0083] 4-(4′-Chlorophenoxy)phenyl sulfonyl chloride (3.0 kg), 3, wasdissolved in three liters of toluene and the solution was addeddropwise, with stirring, to 3.6 kg of trimethyl phosphite which had beenpreheated to 60° C. The reaction was exothermic and the reaction wasallowed to heat to 80°-90° C. during the addition. Thin layerchromatography indicated a mixture of the desired thioether and twobaseline products. The mixture was refluxed until the pot temperaturerose to ˜130° C. The mixture was cooled to ˜60° C. and 1 liter ofmethanol was added. Potassium hydroxide solution (4.5 kg of 45% aqueoussolution) was added dropwise, slowly, with rapid stirring to thereaction mixture. The addition was very exothermic and the pottemperature was controlled to 65°-80° C. The mixture was then refluxedfor 2 hrs. More toluene (6 liters) was added and the mixture cooled to˜60° C. The lower aqueous layer was separated and the organic layerwashed with 3 liters of water. The organic layer was stripped to a lowvolume and 9 liters of isopropanol charged to the hot mixture. Thesolution was distilled until ˜3.5 liters of distillate had beencollected. The mixture was held at 45° C. for several hours and was thencooled to ˜10° C. and stirred several hours. The white, crystallineproduct was collected, washed with cold isopropanol and dried to yield1.9 kg of 4-(4′-chlorophenoxy)phenyl methyl sulfide, 4.

[0084] Step 3

[0085] Into a separate reactor was charged 4-(4′-chlorophenoxy)phenylmethyl sulfide, 4, and CH₂Cl₂ (26 Kg). The resultant solution was cooledto less than 10° C. and then treated with SO₂Cl₂ at such a rate so thatthe temperature did not exceed 10° C. (30 min. required for theaddition). An additional 2 Kg of CH₂Cl₂ was used to rinse in the SO₂Cl₂.After stirring for 1 h, the mixture was warmed to room temperature(degassing occurs) and then further warmed to reflux for 30 minutes.Upon cooling to room temperature, the product solution was washed withwater (15.5 Kg) and then with brine (10.3 Kg). The stirred organicsolution was then treated with a slurry of MgSO₄ (2.6 kg) in CH₂Cl₂ (5kg). The drying was allowed to proceed overnight and the mixture wasfiltered to remove the drying agent. The solids were washed with CH₂Cl₂(20.7 kg) and the combined organics were concentrated to effectazeotropic drying (38 kg of distillate collected, Karl Fischer shows0.026% water in concentrate). The product was treated with CH₂Cl₂ (19.8kg) and then was reconcentrated (19.8 kg distillate, Karl Fischer now at0.014%). HPLC analysis showed 94.7% 4-(4′-chlorophenoxy)phenylchloromethyl sulfide, 5.

[0086] B. Preparation of Silylketene Acetal

[0087] Steps 4 and 5

[0088] Tetrahydropyran-4-carboxylic acid ethyl ester, 9, was preparedfrom commercially available diethylmalonate via steps 4 and 5 usingknown literature procedures as described in for example, U.S. Pat. Nos.5,412,120; 5,414,097; and EP584663 A2.

[0089] Step 6

[0090] To a nitrogen purged reactor was charged 26.8 kg (67.37 mole) ofa solution of LDA. This was cooled to —15° C. and then a mixture ofTMSCl (7.32 kg, 67.37 mole) and tetrahydropyran-4-carboxylic acid ethylester, 9, (10.32 kg, 65.3 mole) was added at such a rate that thetemperature did not exceed −10° C. (1 h addition time). An additional0.2 kg of TMSCl was added in one portion. The resultant mixture washeated to 20° C. and, after 4 h, a vacuum of 28 mm Hg was applied. Themixture was heated to 65° C. to remove volatiles. Toluene (11.95 kg) wasadded and the distillation continued. When no more distillate collected,the mixture was cooled to 25° C. A slurry of celite (2.7 kg) in hexane(20.6 kg) was added. After stirring 1 h, the mixture was filteredthrough a precoated Nutsche filter (1.5 kg of celite in 5 kg of hexanefor precoat). The reactor was rinsed with hexane (11 kg), and this wasused to rinse the filter. The combined organics were concentrated to anoil using 19-25 mm Hg and mild heating. The concentrate was transferredto a nitrogen purged storage vessel with the aid of CH₂Cl₂ (7 kg) togive 17.5 kg of a solution of silylketene acetal 10.

[0091] C. Preparation of4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N-hydroxycarboxamido)Tetrahydropyran

[0092] Step 7

[0093] 90% of the silylketene acetal solution from Step 6 was charged tothe reactor containing 4-(4′-chlorophenoxy)phenyl chloromethyl sulfide5, followed directly by a slurry of ZnCl₂ (0.59 kg, 4.34 mole) in CH₂Cl₂(5 kg). The red reaction mixture was heated to reflux for 14 h (minimalheating required during first 1 h due to exotherm), at which point HPLCshowed about 10% starting material. The remaining 10% of the keteneacetal was added and the mixture was heated at reflux with collection ofthe CH₂Cl₂ to a pot temperature of 68° C. HPLC analysis of an aliquotshowed <1% starting material. Ethanol (15.5 kg), water (20.6 kg), and45% KOH (20.3 kg) were added to the concentrated product mixture. Thetwo phase mixture was stirred at 65° C. overnight (17 h) and was thenwarmed to a pot temperature of 90° C. to complete the saponification andto distill the ethanol. The mixture was cooled to 60-65° C. and hexane(41 kg) was added. After stirring 10 min. and then allowing layerseparation, the lower layer was transferred to another reactorcontaining water (24 kg) and 37% HCl (21.6 kg). Simultaneous with thistransfer, EtOAc (134.5 kg) was pumped to the receiving reactor. Thehexane solution was washed once with 65° C. water (25 liters) which wasthen transferred to the receiving reactor. This reactor now contained anEtOAc solution of the product acid and a lower aqueous layer. The lowerlayer was separated and replaced with 50 L of 65° C. water. Afterstirring briefly, the layers were separated. The organic solution wasconcentrated as much as possible using partial vacuum. CH₃CN (93.5 kg)was added and distillation continued at atmospheric pressure to a finalvolume of 90 liters. The mixture was cooled over 8 h to 5° C. and washeld there 8 h. The solids were collected on a filter and were washedwith CH₃CN (15 kg) and hexane (15.5 kg). After drying at 78° C. and 24mm Hg to constant mass, there was obtained 16.34 kg of the product acid,12, as a dense, slightly off-white solid. HPLC purity was 99%.

[0094] Step 8

[0095] A clean, dry 100 gallon reactor was charged with4-carboxy-4-{4-(4-chlorophenoxyphenyl)thiomethyl}tetrahydropyran 12(15.45 kg, 40.7 moles). To this reactor was added dichloromethane (77.2L, 102 kg). The suspended carboxylic acid was chilled to 0-5° C. underN₂ with agitation. A catalytic amount of N,N-dimethylformamide (0.1 l)was charged, followed by slow addition of oxalyl chloride (5.3 kg, 3.6L). The contents of the reactor were agitated and the internaltemperature was allowed to rise to ambient over a 4-12 hour period toallow conversion to the acid chloride. Another clean, dry 100 gallonreactor was charged with tert-butanol (26.8 kg, 34.5 L), tetrahydrofuran(75.4 kg, 84 L) and hydroxylamine (50 aqueous, 17 kg, 15.8 L). Thecontents of this reactor were agitated at ambient temperature. Thecontents of the reactor containing the acid chloride were chilled to0-5° C. Slow addition of the hydroxylamine solution is begun. The rateof addition was regulated such that the internal temperature of the acidchloride solution does not rise above 10° C. When the addition iscomplete, the contents of the reactor containing the newly formedhydroxamic acid were warmed to 20-25°. After a check for reactioncompleteness (HPLC or TLC), the solvent was removed in vacuo keeping thecontents of this reactor below 45° C. When little solvent is left todistill, the reactor was charged with acetonitrile (48.6 kg, 61.7 L).The contents were heated to reflux, and water (61.7 L) was added over aperiod of 30-50 minutes. The contents of the reactor were cooled to 0-5°C. over a period of 2-4 hours and slowly agitated for 4-14 hours. Thesolid hydroxamic acid 13, was collected by filtration and washed withwater. Typically, the wetcake so obtained is not dried but used as is.However, drying can be accomplished in vacuo at ca 50° C. The solid(21.5 kg wet, 14.45 kg dry, 90.1%) was 99.8% pure by area normalizationHPLC.

[0096] Step 9

[0097] A clean, dry 100-gallon reactor was charged with oxone®(potassium peroxymonosulfate, 37.07 kg, 60.3 moles). Deionized water wasadded (88.3 kg) and the contents of the reactor were agitated and heated(to ca. 35-40° C.) to dissolve the oxone. Another clean, dry 100 gallonreactor was charged with the hydroxamic acid, 13, (21.18 kg waterdampcake, 14.45 dry weight, 36.7 moles) and dissolved inN-methyl-2-pyrrolidinone (100.5 kg) with agitation. The contents of thisreactor were heated to 30-35° C. The aqueous oxone™ solution was addedto the reactor containing the hydroxamic acid at such a rate that theinternal temperature did not exceed 49° C. After the addition of oxone™was complete, the mixture was assayed by HPLC and TLC. When the reactionwas complete, typically in 0 to 1 hour post addition (HPLC data areanormalization purity is typically >98.5% desired product) the productwas treated with deionized water (25 kg) and cooled to 20° C.Crystallization of the crude product typically occurred at 20-25° C.(22° C. in this example). The mixture was then cooled to 5° C. andstirred for 10-14 hours (12 in this example). The precipitated productwas collected by filtration and washed well with deionized waterfollowed by hexanes. This wet cake (47.9 kg) was charged into a clean,dry, residue free 100-gallon reactor. Ethyl acetate (140 kg) was chargedto the solid followed by deionized water (120.6 kg). The contents of thereactor were agitated and heated (to ca 60° C.). Agitation was stoppedand the layers were allowed to separate. The aqueous layer wasseparated. Optionally, this can be followed by an aqueous NaHCO₃ washand water wash. The organic layer was filtered through a 5-10 μ cottonfilter into a clean, dry, residue free reactor. The mixture wasconcentrated in vacuo to approximately 50% (ca 50 L) of the startingvolume. The solid was separated and recrystallized from ethyl acetateafter heating to approximately 70° C. and cooling to 5° C. The solid wascollected by filtration in a clean dry filter and dried at 40-45° C.under a nitrogen stream (an agitated filter was used for this example).11.82 kg of final product,4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N-hydroxycarboxamido)tetrahydropyran, compound 14, was obtained in 75.6% yield (99.8% pure byarea normalization HPLC) upon vacuum drying.

[0098] The foregoing invention has been described in some detail by wayof illustration and example, for the purposes of clarity andunderstanding. It will be obvious to one of ordinary skill in the artthat changes and modifications may be practiced within the scope of theappended claims. Therefore, it is to be understood that the abovedescription is intended to be illustrative and not restrictive. Thescope of the invention should, therefore, be determined with referenceto the following appended claims, along with the full scope ofequivalents to which such claims are entitled.

[0099] The patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

What is claimed is:
 1. A process for the preparation of a compound ofFormula I: Y—C(═O)—C(R¹)(R²)—CH₂—S(O)_(n)R³ wherein: Y is hydroxy orXONX—, where each X is independently hydrogen, lower alkyl or loweracyl; R¹ is hydrogen or lower alkyl; R² is hydrogen, lower alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, or R¹ and R²together with thecarbon atom to which they are attached form a cycloalkyl or heterocyclogroup; R³ is aryl; and n is 0, 1 or 2; comprising the steps of: (1)alkylating a compound of Formula II, RO—C(═O)—CH(R¹)(R²), where R isalkyl or hydrogen, with an arylmethylthio derivative of Formula III,ArSCH₂—Z, wherein Ar is an aryl group and Z is a leaving group, toprovide a compound of Formula IV, RO—C(═O)—C(R¹)(R²)—CH₂SAr; and (2)converting the compound of Formula IV to a compound of Formula I byreplacing the group RO— with XONX— and optionally oxidizing the ArSgroup.
 2. The method of claim 1, wherein: Ar has the formula Ar¹—A—Ar²where Ar¹ and Ar² are phenyl rings, each independently optionallysubstituted and A is a bond, —CH₂— or —O—.
 3. The method of claim 2,wherein Z is halo.
 4. The method of claim 3, wherein: A is oxygen; Ar¹is phenyl; and Ar² is 4-chlorophenyl.
 5. The method of claim 4, whereinthe optional oxidation in step (2) provides a compound of Formula Iwhere n=2.
 6. The method of claim 5, wherein R¹ and R² together with thecarbon atom to which they are attached form a heterocyclo group.
 7. Themethod of claim 6, wherein the heterocyclo group formed by R¹ and R² istetrahydropyranyl.
 8. The method of claim 7, wherein the compound ofFormula I is4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N-hydroxycarboxamido)tetrahydropyran.
 9. The method of claim 2, which further comprisesforming the compound of Formula III, Ar¹—A—Ar²—SCH₂—Z by: (i) treating acompound of Formula VI, Ar¹—A—Ar²—S(O)₂Cl with trimethyl phosphite, (ii)optionally, followed by treatment with a base, and (iii) oxidation. 10.The method of claim 9, wherein: Ar¹ is phenyl; Ar² is 4-chlorophenyl; Ais oxygen; R¹ and R² together with the carbon atom to which they areattached form a tetrahydropyranyl group; and Y is HONH.
 11. The methodof claim 4, wherein step (1) comprises converting a compound of FormulaII to a silylketene acetal of Formula V, RO(OTMS)C═CR¹R², and alkylatingthe silylketene acetal with a compound of Formula III.
 12. The method ofclaim 4, wherein step (1) comprises alkylating an enolate of a compoundof Formula II with a compound of Formula III.
 13. A method of preparinga compound of Formula ArSCH₃, wherein Ar is an aryl group, by treating acompound of Formula ArSO₂Cl with trimethyl phosphite and optionally,followed by a base, to form a compound of Formula ArSCH₃.
 14. The methodof claim 13, wherein Ar has the formula Ar¹—A—Ar², where Ar¹ and Ar² arephenyl rings, each independently optionally substituted and A is a bond,CH₂ or —O—.
 15. The method of claim 14, wherein: A is oxygen; Ar¹ isphenyl; and Ar² is 4-chlorophenyl.
 16. A compound ZCH₂S—Ar¹—A—Ar²,wherein: Ar¹ and Ar² are independently optionally substituted phenyl; Zis halo; and A is oxygen or CH₂.
 17. The compound of claim 16, wherein:Ar¹ is phenyl; Ar² is halophenyl; and A is oxygen.
 18. The compound ofclaim 17 wherein Ar² is chlorophenyl, and Z is chloro, i.e.,4-(4-chlorophenoxy)phenyl chloromethyl sulfide.
 19. The compound whichis 4-(4-chlorophenoxy)phenyl methyl sulfide.